March 07, 2023: Prophylactic Antibodies

Alter Vaccine Responses To Covid - 19

We are now in the third year of the Covid-19 pandemic. It is likely that Covid and the virus that causes it will be with us for many years. Most of us already have a complex history with Covid-19, including infection by the virus and exposure to a mix of vaccines and antiviral drugs. It is time to examine how the interplay of infections, antiviral drugs, and vaccines condition our response to new infections. Such a study is critical, as we now know that longterm protection from disease depends on the efficacy of memory response, not on initial neutralizing responses.

A recent study by Schaefer-Babajew et al. in the journal Nature begins to do just that by examining the influence of prophylactic antibody treatment on our antibody and memory B cells' response to vaccines. Surprisingly, they find that protective antibody treatments significantly affect our B cell memory response and may diminish the ability of vaccines to protect us from serious diseases.

StudyDesign

Schaefer-Babajew et al. examined a cohort of 18 patients who received a combination antibody treatment of C144-LS and C135LS, a combination yet to be approved or authorized for public use in the United States. Both of these antibodies bind to different regions of the receptor-binding domain and together have significant neutralizing potency against authentic SARS-CoV-2 wild-type virus obtained from human patients.

These antibodies were first described by Robbiani et al . in June 2020. C144 and C135 were isolated along with 50 other neutralizing antibodies from the sera of over 150 patients infected with SARS-CoV-2 in the early months of the pandemic. C144 and C135 were later modified with the ‘LS mutations,’ which is a method of improving the half-life of an antibody by enhancing the binding affinity between the Fc of an antibody and the human Fc receptor.

The cohort examined by Schaefer-Babajew et al. participated in a preliminary study to test the efficacy of these antibodies for submission to the Food and Drug Administration for emergency use authorization or approval. However, neither antibody is approved or authorized today. No patients in this study, whether experimental or control, were infected by SARS-CoV-2 before this study.

The 18 patients then received a two-dose mRNA vaccine regimen after a median of 82 days for the first dose and 103 days for the second. The cohort was compared to another group of patients vaccinated with two mRNA doses but with no previous history of infection or monoclonal antibody treatment. Patients received either the Moderna or Pfizer-BioNTech mRNA vaccine. The researchers examined the antibody binding, antibody neutralization, memory B cells, and antibodies produced by memory B cells.

TheEffectofPriorTreatment on AntibodiesthatBindtheSpike Protein

The first query was whether previous antibody treatment impacted antibody binding in patient sera. They examined the binding levels of two antibody types: IgM, which arises earlier in infection, and

IgG, which is the most common type of antibody and is typically the type used for antibody treatments.

The IgM antibody binding efficiency between treatment and nontreatment patients was relatively stable. For IgG antibodies, binding in the treatment group rose above the non-treatment after the first dose, but stabilized after the second. These results, however, were solely when tested against the wild-type Wuhan virus. When tested against a virus coded with receptor-binding domain mutations R346S/E484K or N440K/E484K, directly interfering with the epitope for both C144 and C135 binding, efficiency drops below the non-treatment group, though only marginally. The pseudovirus was also encoded with mutation R683G, far from the epitope involved with C144 and C135. The mutation disrupts the function of the furin-cleavage site, increasing particle infectivity without compromising the binding affinity between the receptorbinding domain and the antibodies.

Ultimately, the results show that monoclonal antibody infusions have little to no impact on IgM and IgG binding responses.

TheEffectofPriorTreatment on VirusNeutralization

They next examined the effect of infused antibody treatment on post-vaccine neutralization. They again introduced C144 and C135 to a wild-type spike protein pseudovirus and a mutated version.

Against the wild-type, those who received the antibodies beforehand had significantly higher neutralizing titers after both the first and second doses. Their past monoclonal treatment enhanced their post-vaccine defense against the virus.

For the following mutated pseudoviruses, the antibodies made a negative impact rather than a positive one. The researchers introduced patient sera to pseudoviruses with R346S/Q493K and R346S/N440K/E484K mutations. Once again, R346S, N440K, Q493K, and E484K directly interfere with the binding epitopes of C144 and C135. After the first dose, those in the antibody group saw neutralizing titers fall 2.7-fold and 3.5-fold against the mutant viruses compared to the control group.

Neutralization rebounds to just a 0.6-fold to 0.85-fold drop from the control group after the second vaccination, which is less statistically significant, though still relevant. Against highly mutated spike proteins, previous antibody treatments may lower your immune defenses post-vaccination. This is notable as all viruses circulating today are heavily mutated in the receptor-binding domain, potentially causing concern for those with many previous antibody treatments.

TheEffectofPriorTreatment on Memory BCells

Perhaps the researchers’ most crucial finding relates to memory B cell responses. One critical aspect of memory is the persistence of memory B cells. These cells have full antibody maturation and are stable for months or even years. Reinfection by a similar virus causes rapid proliferation and production of protective B cell antibodies.

Schaefer-Babajew et al. found that mRNA vaccination elicited memory B cell responses approximately three-fold higher in the antibody group than in the control.